A substantial component of NAS research utilizes on a rat model of cognitive aging validated over the course of many earlier studies. Important features of the model are that outbred, Specific Pathogen Free Long-Evans rats are tested using a sparse training protocol in a version of the Morris water maze optimally tuned to interrogate the functional integrity of the hippocampus. This protocol reveals prominent and reliable individual differences in spatial learning and memory at 24+ months of age, with impairment qualitatively similar to the effects of hippocampal damage in young subjects. After excluding subjects with sensorimotor deficits that might be misinterpreted as cognitive impairment, spatial learning capacities among the aged rats are continuously distributed across a broad range from substantial deficits to fully intact performance on par with young adults. In this way the model enables comparisons across subjects matched according to chronological age but distinguished by differences in the status of hippocampal memory. Previous studies confirm that behavioral outcomes in this setting provide a valuable framework for exploring the neurobiology of cognitive aging, and for developing potential therapeutic interventions. Significant progress during the reporting period has been realized on several fronts. Mounting evidence indicates that histone acetylation dynamics in the hippocampus regulate plasticity critical for long-term memory. How experience interacts with histone acetylation levels to modulate downstream gene and protein expression, however, is not well understood. In an ongoing series of studies exploring this issue, for example, we tested the individual and combined effects of acute histone deacetylase inhibitor (HDACi) administration and water maze training on gene expression in the principal cell fields of the hippocampus. Behavioral training powerfully modulated the response to HDACi treatment, increasing the number of genes regulated nearly 10-fold. The effect of behavioral training alone was also substantial, but the specific genes and gene networks affected were largely non-overlapping with the influence of the same experience provided together with HDACi administration. A parallel study examined the interactive influence of recent experience and HDACi treatment on synaptic protein expression, and tested the possibility that the effect of these treatments on hippocampal plasticity is altered in aged rats with memory impairment. Complementing the results for gene expression, synaptic protein levels were only elevated in the young adult hippocampus when HDACi administration was provided in conjunction with behavioral training, and moreover, this response was completely absent in the aged hippocampus. The significant implication for the development of therapeutic strategies targeting epigenetic control is that the response to treatment may vary markedly in relation to an individual's unique history and ongoing behavior, and that the capacity for regulation is blunted in aging. In a related ongoing inter-laboratory collaboration we are using current generation sequencing methods to test the possibility that nucleosome occupancy and positioning is altered in the aged hippocampus, and that these effects are coupled with corresponding effects on gene transcription. Together this work extends our recent investigations exploring the cognitive effects of pharmacological treatments targeting epigenetic control, and studies examining the role of epigenetic regulation in a mouse model of brain amyloid deposition. Other recent project efforts focus on a neural systems and network level of analysis, testing the possibility that cognitive aging arises from disruption in the large-scale organization and interaction between anatomically or neurochemically defined circuits. In a collaborative study with investigators in the Neuroimaging Research Branch at NIDA, for example, we used in vivo brain imaging methods in our established rat model to test whether disrupted functional connectivity across key components of the default mode network is coupled with individual differences in cognitive outcome. Indeed all aged rats that displayed decreased connectivity exhibited memory impairment, although memory impairment was observed in some aged individuals with normal resting state dynamics. Aged rats with preserved memory, by comparison, displayed a qualitatively different pattern, distinct from both young and memory-impaired aged cohorts. These findings are consistent with the idea that healthy cognitive aging comprises a process of active adaptation, and not simply a slower rate of aging. To the best of our knowledge this is also the first demonstration of disrupted resting state activity in relation to aging in a preclinical animal model. Studies of this sort will ultimately establish the foundation for longitudinal analyses testing potential intervention strategies, providing a translational bridge to related human research.